1. Field of the Invention
The present invention is directed to phenyl compounds substituted with a fused-heterobicyclo moeity. In particular, this invention is directed to phenyl compounds substituted at the 1-position with a fused bicyclo moeity formed from a five-membered heterocycle fused to a six-membered carbocycle, to a six-membered aryl, or to a six-membered hetaryl, and further optionally substituted at the 3,4 positions, which are modulators of metabotropic glutamate receptor—subtype 5 (“mGluR5”) modulators useful in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, and panic, as well as in the treatment of pain, Parkinson's disease, cognitive dysfunction, epilepsy, drug addiction, drug abuse, drug withdrawal and other diseases.
2. Related Background
A major excitatory neurotransmitter in the mammalian nervous system is the glutamate molecule, which binds to neurons, thereby activating cell surface receptors. Such surface receptors are characterized as either ionotropic or metabotropic glutamate receptors. The metabotropic glutamate receptors (“mGluR”) are G protein-coupled receptors that activate intracellular second messenger systems when bound to glutamate. Activation of mGluR results in a variety of cellular responses. In particular, mgluR1 and mgluR5 activate phospholipase C, which is followed by mobilizing intracellular calcium.
Modulation of metabotropic glutamate receptor subtype 5 (mGluR5) is useful in the treatment of diseases that affect the nervous system (see for example W. P. J. M Spooren et al., Trends Pharmacol. Sci., 22:331–337(2001) and references cited therein). For example, recent evidence demonstrates the involvement of mGluR5 in nociceptive processes and that modulation of mGluR5 using mGluR5-selective compounds is useful in the treatment of various pain states, including acute, persistent and chronic pain [K Walker et al., Neuropharmacology, 40:1–9(2001); F. Bordi, A. Ugolini Brain Res., 871:223–233(2001)], inflammatory pain [K Walker et al., Neuropharmacology, 40:10–19(2001); Bhave et al. Nature Neurosci. 4:417–423(2001)] and neuropathic pain [Dogrul et al. Neurosci. Lett. 292:115–118(2000)].
Further evidence supports the use of modulators of mGluR5 in the treatment of psychiatric and neurological disorders. For example, mGluR5-selective compounds such as 2-methyl-6-(phenylethynyl)-pyridine (“MPEP”) are effective in animal models of mood disorders, including anxiety and depression [W. P. J. M Spooren et al., J. Pharmacol. Exp. Ther., 295:1267–1275(2000); E. Tatarczynska et al, Brit. J. Pharmacol., 132:1423–1430(2001); A. Klodzynska et al, Pol. J. Pharmacol., 132:1423–1430(2001)]. Gene expression data from humans indicate that modulation of mGluR5 may be useful for the treatment of schizophrenia [T. Ohnuma et al, Mol. Brain. Res., 56:207–217(1998); ibid, Mol. Brain. Res., 85:24–31(2000)]. Studies have also shown a role form GluR5, and the potential utility of mGluR5-modulatory compounds, play in the treatment of movement disorders such as Parkinson's disease [W. P. J. M Spooren et al., Europ. J. Pharmacol. 406:403–410(2000); H. Awad et al., J. Neurosci. 20:7871–7879(2000); K. Ossawa et al. Neuropharmacol. 41:413–420(2001)]. Other research supports a role form GluR5 modulation in the treatment of cognitive dysfunction [G. Riedel et al, Neuropharmacol. 39:1943–1951(2000)], epilepsy [A. Chapman et al, Neuropharmacol. 39:1567–1574(2000)] and neuroprotection [V. Bruno et al, Neuropharmacol. 39:2223–2230(2000)]. Studies with mGluR5 knockout mice and MPEP also suggest that modulation of these receptors may be useful in the treatment of drug addiction, drug abuse and drug withdrawal [C. Chiamulera et al. Nature Neurosci. 4:873–874(2001)].
International Patent Publications WO 01/12627 and WO 99/26927 describe heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists. International Patent Publications WO 96/05818, WO 00/73283, WO 00/20001, and U.S. Pat. No. 6,031,003 describe polycyclic compounds active at metabotropic glutamate receptors.
Russian Patent Nos. SU 1824402, SU 1830388, and SU 1806138 describe processes for producing 2-phenylbenzoxazole. Japanese Patent No. JP 07013369 describes an electrophotographic photoreceptor containing oxazole or thiazole derivative charge-transporting agents. International Patent Publication EP 479161 describes the synthesis of heterocyclic compounds. Japanese Patent No. JP 55038302 describes benzoxazole derivatives. German Patent No. DE 2619547 and U.S. Pat. No. 4,107,169 describe 2-arylbenzoxazoles and 2-arylbenzothiazoles. U.S. Pat. Nos. 3,772,309, and 3,630,972 describe 2-arylbenzazoles and polybenzimidazoles. German Patent Nos. DE 2037998 and DE 2037999 describe benzazoles, benzazolinones, quinolines, indoles, benzothiazoles, benzimidazoles, and benzoxazoles. U.S. Pat. No. 3,452,036 and Japanese Patent No. JP 42015938 describe 2-substituted benzoxazoles. Dutch Patent No. NL 6607039 describes herbicidal benzazoles.
International Patent Publication No. WO 9427601 describes the preparation of [(benzoxazolylphenyl)alkoxy]alkylamines as squalene synthase inhibitors. U.S. Pat. No. 3,458,506 describes fluorescent benzazoles compounds containing cyanovinylene groups.
U.S. Pat. No. 3,647,809 describes pyridyl-1,2,4-oxadiazole derivatives. U.S. Pat. No. 4,022,901 describes 3-pyridyl-5-isothiocyanophenyl oxadiazoles. International Patent Publication WO 98/17652 describes oxadiazoles, WO 97/03967 describes various substituted aromatic compounds, and WO 94/22846 describes various heterocyclic compounds.
Compounds that include ringed systems are described by various investigators as effective for a variety of therapies and utilities. For example, International Patent Publication No. WO 98/25883 describes ketobenzamides as calpain inhibitors, European Patent Publication No. EP 811610 and U.S. Pat. Nos. 5,679,712, 5,693,672 and 5,747,541 describe substituted benzoylguanidine sodium channel blockers, and U.S. Pat. No. 5,736,297 describes ring systems useful as a photosensitive composition.
The following compounds are available from Maybridge plc, Cornwall, England:

However, there remains a need for novel compounds and compositions that therapeutically inhibit mGluR5 with minimal side effects.